Antibiotic compostions and methods for using same

ABSTRACT

Compositions including a quinolone component in an amount effective as an antibiotic when the composition is placed in a mammalian eye, and a carrier component in an amount effective to act as a carrier for the quinolone component are provided. The present compositions are substantially free of other components effective as preservatives. Preferably the quinolone component has fungistatic activity. In one very useful embodiment, the compositions include a NSAID component in an amount effective to reduce inflammation or pain when the composition is placed in a mammalian eye. Methods of using the present compositions, for example, to resolve microbial infections and/or to reduce inflammation and/or pain in a mammalian eye are included within the scope of the present invention.

BACKGROUND OF THE INVENTION

The present invention relates to antibiotic compositions and to methodsfor using such compositions. More particularly, the invention relates toantibiotic compositions which are effective in use and reduce the risksof harmful side effects, such as, irritation, on the body part, forexample, the eye, being treated.

Various antibiotic components have been used in ocular applications, forexample, to control or manage or prevent ocular infections and the like.Moreover, antibiotic components, such as tobramycin have been suggestedfor use in combination with other materials, such as ophthalmicallyacceptable non-steroidal anti-inflammatory drugs or NSAIDs. See, forexample, Fu et al. U.S. Pat. No. 5,414,011, the disclosure of which isincorporated in its entirety herein by reference. Quinolones, such asofloxacin, have been used in compositions for treating ocularinfections. These antibiotic compositions include one or more additionalcomponents which act as preservatives, for example, benzalkoniumchloride (BAK) or organomercurials.

However, the use of BAK, organomercurials or other preservativecomponents may be problematic. For example, BAK may be incompatible withcertain active components and organomercurials pose difficulties due topotential mercury toxicity, as well as poor chemical stability. Althoughthese problems may be significant, a more pervasive and common concerncaused by preservatives components is the tendency of such components tocause irritation, allergic reactions, and/or other detrimental sideeffects when the preserved composition is administered to a patient.

It would be advantageous to provide stable, effective antibioticcompositions, and methods for using such compositions, that providereduced risks of irritation and/or other harmful side effects caused bypreservatives typically present in such compositions.

SUMMARY OF THE INVENTION

New antibiotic compositions, for example, for use in mammalian eyes,preferably human eyes, and methods for using such compositions have beendiscovered. By administering present compositions to humans or animals,for example, to the eyes of humans or animals, desired therapeuticeffects are provided, such as the prevention, control or management ofocular microbial infections, reductions in inflammation and/or pain andthe like. Importantly, the present compositions are substantially freeof added or separate preservatives. This feature provides substantialbenefits, for example, substantial elimination of irritation and/orother detrimental effects which may be caused by the presence of suchadded preservative components. The present compositions can be easilyproduced, for example, using conventional techniques and can beconveniently used, for example, employing conventional methods ofadministration.

In accordance with one aspect of the invention, the compositionscomprise a quinolone component and a carrier component. The compositionsare substantially free of other components effective as preservatives.The quinolone component is present in an amount effective as aantibiotic when the composition is placed in a mammalian eye. In oneuseful embodiment, the quinolone component in the composition hasfungistatic activity. That is, the quinolone components in the presentcompositions may have sufficient anti-fungal properties or activity tosubstantially prevent increases in populations of fungi in suchcompositions. In effect, the present quinolone components may act aseffective preservatives against fungal growth in the presentcompositions. The carrier component is present in an amount effective toact as a carrier for the quinolone component, and other active componentor components, if present, in the composition, and preferably isophthalmically acceptable.

In one very useful embodiment, the present compositions comprise aquinolone component, a non-steroidal anti-inflammatory drug (NSAID)component, and a carrier component effective to act as a carrier for thequinolone and NSAID components. The quinolone component is effective asan antibiotic, as described elsewhere herein. The NSAID component ispresent in an amount effective to reduce at least one of inflammationand pain when the composition is placed in a mammalian eye.

The present compositions preferably include a quinolone component whichis halogenated, more preferably fluorinated. Very useful compositionsand results are obtained when the quinolone component is an ofloxacincomponent.

Although any NSAID component may be used, the NSAID components includedin the present compositions preferably are carboxylic (—COOH)group-containing NSAID components. More preferably, the NSAID componentis a pyrrolo pyrrole component, still more preferably a ketorolaccomponent.

The present carrier components may contain one or more pharmaceuticallyor ophthalmically acceptable ingredients, for example, tonicity adjustercomponents, buffer components, viscosity components, lubricitycomponents, surfactant components and the like, conventionally used, forexample, in ophthalmic formulations. Preferably, the compositions havepH's in the physiological range of human beings, for example, in therange of about 4 to about 8.5.

The present compositions may be in any form suitable for effectiveadministration to the human or animal to be treated. Preferably, thecompositions are present in a form selected from solutions, suspensions,gels, ointments solids and the like which are very effective for ocularadministration. The carrier component may conveniently be selectedand/or compounded to provide the composition in the form desired.

Methods of using these compositions are included in the scope of thepresent invention. Such methods comprise administering to a human oranimal, preferably to a mammalian eye, a therapeutically effectiveamounts of the compositions as described herein. Such methods provideone or more benefits to the human or animal treated in accordance withthe present methods. For example, such benefits include prevention,control or management of is microbial infections, and reduction ininflammation and/or pain. Because the present compositions include noadditional preservatives, the human or animal being treated is subjectedto reduced risks of irritation and/or other detrimental or unpleasantside effects caused by the presence of such preservatives.

Any and all features described herein and combinations of such featuresare included within the scope of the present invention provided that thefeatures of any such combination are not mutually inconsistent.

These and other aspects and advantages of the present invention are inthe following detailed description and Examples and claims.

DETAILED DESCRIPTION

The present compositions comprise quinolone components and carriercomponents. Importantly, the present compositions are substantially freeof other components effective as preservatives. Such substantiallypreservative-free compositions remain effective to provide the desiredantibiotic effectiveness of the present compositions, while at the sametime reducing the risk of irritation and/or other uncomfortable sideeffects caused by the presence of one or more added preservatives. Eventhough the present compositions are substantially preservative-free, ithas been found that the present compositions have sufficientpreservative efficacy to meet or exceed the standards of the UnitedStates Preservative Efficacy Test (USPET).

The present compositions include quinolone components. A number of suchquinolone components are known and have been used for many years inantibiotic applications. For example, nalidixic acid has been availablefor the treatment of urinary tract infections. The useful quinolonecomponents preferably are four-quinolones that contain a carboxylicmoiety in the three position of the basic structure shown below:

Preferably, the present quinolone components exhibit fungistaticproperties in the present compositions. That is, the quinolonecomponents in the present compositions preferably are effective topreserve the present composition against population growth of fungi,such as C. Albicans and A. niger.

The present quinolone components preferably are halogenated. Forexample, a chlorinated quinolone component, such as9-chloro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyridol[1,2,3-de][1,4]benzozaxine-6 carboxylic acid may be used.

More preferably, the present quinolone components are fluorinated.Examples of such fluorinated quinolones include norfloxacin,ciprofloxacin and ofloxacin. Such fluorinated quinolone components arehighly effective against a range of bacteria and are useful in treatingvarious microbial infections in the mammalian eye. Priorofloxacin-containing compositions including such quinolone used for thispurpose include additional preservatives, for example, BAK. Thus, whilethe quinolone is effective against the ocular infection, thepreservatives present in such compositions may cause undesirableirritation and/or other disadvantageous side effects.

It has been found that the present quinolone components, such asofloxacin, are very effective when present in compositions includingsubstantially no additional components which are effective aspreservatives. Moreover, quinolones, such as ofloxacin, have been foundto have sufficient fungistatic activity to be useful in the presentcompositions to act as a preservative against fungal contamination. Asnoted previously, the present compositions including such quinolonecomponents with no additional preservative components is sufficientlypreserved so as to pass the USPET.

The present compositions include an antibiotically effective amount ofthe quinolone component. Such amounts may vary over a relatively broadrange depending, for example, on the specific form of the compositionbeing used, the specific quinolone component being used, the specificapplication for the composition, the frequency of use of the compositionand the like factors. In many situations, the present compositions mayinclude a quinolone component in an amount in a range of about 0.03%(w/v) or less to about 3% (w/v) or more. Preferably, the presentcompositions include the quinolone component in an amount in the rangeof about 0.15% (w/v) to about 0.5% (w/v) or about 1.1% (w/v).

The quinolone component may be any quinolone derivative which isacceptable or suitable for administration to the eye and has at least aportion, preferably a major portion or at least about 50% of theantibiotic effectiveness of the basic quinolone in the presentcomposition in the mammalian eye. The present quinolone component may beselected from the quinolone itself or quinolone hydrates orophthalmically acceptable salts of such quinolones, for example,including acid addition salts such as hydrochlorides, maleates, pamoatesand the like, and alkali metal salts such as sodium and potassium salts,and mixtures thereof and the like.

The present carrier components may be selected from pharmaceuticallyacceptable organic and/or inorganic components which, preferably, in thepresent compositions are ophthalmically acceptable. As used herein, theterm “ophthalmically acceptable” refers to a material which, at theconcentration or amount in question, is compatible with ocular tissue,that is the material does not cause significant or undue detrimentaleffects when brought into contact with ocular tissue. The carriercomponent preferably is ophthalmically acceptable. Preferably, eachcomponent of the present compositions is also compatible with the othercomponents of the compositions.

Examples of suitable materials useful in the present carrier componentsinclude water, mixtures of water and water-miscible solvents such aslower alkanols or aralkanols, vegetable oils, polyalkylene glycols,petroleum-based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl mirstate, otherconventionally employed pharmaceutically acceptable materials and thelike.

The carrier component may also include auxiliary substances such asemulsifiers, wetting agents, bodying agents, buffer components, acidsand/or bases, tonicity adjuster components, surfactant components,viscosity agents, lubricity components, other materials useful inophthalmic formulations and the like.

Examples of optionally useful bodying agents include, but are notlimited to, various polyethylene glycols, carbowaxes, petroleum jellyand the like.

Suitable buffers include, but are not limited to, inorganic buffers suchas phosphate buffers, borate buffers and the like, and organic buffers,such as acetate buffers, citrate buffers, tromethamine and the like.

Tonicity adjusters optionally useful in the present compositionsinclude, but are not limited to, dextrose, potassium chloride and/orsodium chloride and the like, preferably sodium chloride.

Acids optionally useful in the present compositions include boric acid,hydrochloric acid, acetic acid, other acids which are ophthalmicallyacceptable in the concentrations used, and the like.

Bases which may be included in the present compositions include, but arenot limited to, sodium and/or potassium hydroxides, other alkali and/oralkaline earth metal hydroxides, organic bases, other bases which areophthalmically acceptable in the concentrations used, and the like.

The acid/bases/buffers preferably are included, if at all, to provideand/or maintain the present compositions at a pH in the physiologicallyacceptable range, more preferably in a range of about 4 to about 8.5,still more preferably about 6 to about 8, and especially about 6.8 toabout 8.

Surfactant components optionally useful in the compositions of thepresent invention include, but are not limited to, lipoproteindetergents that when present in the compositions reduce the surfacetension between the compositions and the eye (lacrimal) fluid.Preferably, nonionic surfactants are used.

Viscosity agents optionally useful in the compositions of the presentinvention include, but are not limited to, carbopol, cellulosederivatives such as hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, other viscosity inducing materialsuseful in ophthalmic formulations and the like.

Lubricity components optionally useful in the compositions of thepresent invention include, but are not limited to, polyvinyl alcohol,polyvinylpyrrolidone, carbopol and the like.

The present compositions may include effective amounts of chelating orsequestering components, such as ethylene diamine tetraacetic acid(EDTA), citric acid, tartaric acid and the like. In one usefulembodiment, the present compositions are substantially free of EDTA.

Other optional excipients useful in the present compositions includestabilizing agents such as antioxidants, for example, alkali metalmetabisulfates, ascorbic acid and the like.

The carrier component may be in various forms. In one embodiment, thecarrier component comprises a liquid, and the composition may be asolution or a suspension. In either situation, the carrier may simplycontain water and one or more auxiliary components noted elsewhereherein.

The present compositions may be in any suitable form effective to beadministered to the eye. Such forms include solutions, suspensions,ointments, gels, solids and the like. An ointment may be considered as aform intermediate between a suspension and a gel. Each of these forms ofthe present compositions can be prepared using techniques and processingwhich are conventional and well known in the art.

In another embodiment, the carrier component may be in the form of aclear material which forms a semi-solid “gel” at human bodytemperatures. Various polymers, many of which are conventional and wellknown in the art, can be included in the carrier components to providethe present compositions in the form of gels. For example, a polymersystem including alkylene diamine tetra substituted with about 40% toabout 80% poly(oxyethelene) units and about 20% to about 60%poly(oxypropylene) units may be employed. The molecular weight of thepolymer used preferably is at least about 7,000 and can be as high asabout 50,000, more preferably in the range of about 7,000 to about30,000. The gel forming component, if any is present in an amounteffective to provide the composition in the form of a gel. For example,such gel forming component may be present in an amount in a range ofabout 10% or less to about 50% or more by weight of the total carriercomponent.

The compositions may also be in the form of solid inserts, for example asolid dosage form that is suitable for insertion into the cul-de-sac ofa mammalian eye. To this end, the composition components can be includedwith a non-bioerodible insert, for example, one which after dispensingthe active component or components remains essentially intact, or abio-erodible insert, for example, one that either is soluble in lacrimalfluids, or otherwise disintegrates.

A solid water soluble polymer may be employed in the carrier component.Such polymers include, for example, cellulose derivatives such asmethylcellulose, sodium carboxymethyl cellulose, or a hydroxy loweralkyl cellulose such as hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose and the like; acrylates such aspolyacrylic acid salts, ethyl acrylates, polyacrylamides, naturalproducts such as gelatin, alginates, pectins, tragacanth, daraya,chondrus, agar, acacia; the starch derivatives such as starch acetate,hydroxyethyl starch ethers, hydroxypropy starch, as well as othersynthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone,polyvinyl methyl ether, polyethylene oxide, neutralized carbopol andxanthan gum, mixtures thereof and the like.

In another useful embodiment, the present compositions further include aNSAID component, in addition to the quinolone component and the carriercomponent, in an amount effective to reduce inflammation and/or painwhen the compositions are administered to a mammalian eye, for example,to prevent or treat diseases which are either caused by, associated withor accompanied by inflammatory processes and/or pain, including, amongothers, glaucoma, cystoid macular edema, uveitis, diabetic retinopathyand conjunctivitis, or any trauma caused by eye surgery or eye injury.

The NSAID component may or may not include a carboxylic (—COOH) group ormoiety, or a carboxylic derived group or moiety. In one embodiment, theNSAID component inhibits the cyclo-oxygenase enzyme, which has two (2)isoforms, referred to as COX-1 and COX-2. Many of the well known NSAIDcomponents are basically non-selective COX inhibitors. NSAID componentswhich are selective COX-2 inhibitors are also known. Both types of NSAIDcomponents, that is both non-selective COX inhibitors and selectiveCOX-2 inhibitors are useful in accordance with the present invention.The NSAID component may be selected from phenylalkanoic acids, such asdiclofenac, flurbiprofen, ketorolac, piroxicam and the like; indoles,such as indomethacin and the like; diarylpyrazoles, such as celecoxiband the like; pyrrolo pyrroles; and other agents that inhibitprostaglandin synthesis. A very useful NSAID component is the pyrrolopyrrole which has a propionic acid moiety, known as ketorolac andderivatives thereof, such as non-toxic esters and salts thereof. Pyrrolopyrroles have been suggested for use in the treatment of certainophthalmic diseases in Waterbury U.S. Pat. No. 4,454,151, the disclosureof which is incorporated in its entirety herein by reference.

The NSAID component may be present in the present compositions in anysuitable concentration effective to reduce inflammation or pain when thecomposition is placed in a mammalian eye. For example, the NSAIDcomponent, if present at all, preferably is present in an amount in arange of about 0.001% (w/v) or less to about 10% (w/v) or more, and morepreferably in a range of about 0.02% (w/v) to about 0.5% (w/v) or about1% (w/v).

The present compositions may be prepared using conventional techniques,for example, by formation of solutions, gels, suspensions, etc., usingwell known and conventional techniques. For a more detailed discussionof the preparation and administration of ophthalmic formulations seeRemingtons Pharmaceutical Sciences, 15 Ed., Pgs. 1489 to 1504 (1975)which is incorporated in its entirety herein by reference.

In general, the present methods for treating mammalian eyes compriseadministering to the mammalian eye a therapeutically effective amount ofthe present composition thereby providing an effective antibiotic in themammalian eye, and, if NSAID component is present in the composition,thereby reducing inflammation or pain in the mammalian eye. The presentmethods of use may involve any suitable administration step or steps toprovide an effective amount of the composition to the mammalian eye.Such administering may include, but is not limited to, topicalapplication to the eye, instillation into the eye, placing an insertinto the cul-de-sac (space) between the eyeball and the eyelid and thelike. Other conventional methods of administering compositions to theeye may be employed provided that the present compositions areadministered so as to provide the benefits desired.

The present use methods may be considered to be curative and/orpreventative when applied, presurgically or s immediately posttraumatically, that is before a microbial infection develops, or beforeinflammation and/or pain is apparent. The present use methods areeffective to reduce the risk of the formation of such infections and toreduce the severity of any inflammation or pain which may develop.

The dosage level of the present composition depends, of course, on manyfactors, for example, the particular application involved, theparticular active component or components employed, the concentration ofthe active component or components in the composition, the severity ofthe infection/inflammation/pain and the individual's response to thetreatment. Such dosage can be easily determined by routine and wellknown techniques to achieve the desired results in the individualpatient being treated.

The following non-limiting examples illustrate certain aspects of thepresent invention.

EXAMPLES 1 TO 11

A series of compositions, Compositions 1 to 11, are prepared by blendingvarious components together. These compositions have the followingchemical make-ups.

Composition 1

Ofloxacin  0.6 w/v % NaCl 0.79 w/v % pH 6.4 water q.s. 100%

Composition 2

Ofloxacin  1.0 w/v % NaCl 0.79 w/v % pH 6.4 water q.s. 100%

Composition 3

Ofloxacin 0.6 w/v % NaCl 0.3 w/v % EDTA 0.1 wt % Boric Acid 1.0 w/v % pH6.4 water q.s. 100%

Composition 4

Ofloxacin 1.0 w/v % NaCl 0.3 w/v % EDTA 0.1 wt % Boric Acid 1.0 w/v % pH6.4 water q.s. 100%

Composition 5

Ketorolac 0.5 w/v % Ofloxacin 0.6 w/v % NaCl 0.79 w/v %  pH 6.4 waterq.s. 100%

Composition 6

Ketorolac 0.5 w/v % Ofloxacin 1.0 w/v % NaCl 0.79 w/v %  pH 6.4 waterq.s. 100%

Composition 7

Ketorolac 0.5 w/v % Ofloxacin 0.6 w/v % NaCl 0.3 w/v % EDTA 0.1 w/v %Boric Acid 1.0 w/v % pH 6.4 water q.s. 100%

Composition 8

Ketorolac 0.5 w/v % Ofloxacin 1.0 w/v % NaCl 0.3 w/v % EDTA 0.1 w/v %Boric Acid 1.0 w/v % pH 6.4 water q.s. 100%

Composition 9

Ketorolac 0.5 w/v % Ofloxacin 0.3 w/v % NaCl 0.79 w/v %  BAK 0.005 w/v%  L-Arginine 0.28 w/v %  pH 6.4 water q.s. 100%

Composition 10

Ketorolac 0.5 w/v % Ofloxacin 0.3 w/v % NaCl 0.79 w/v %  BAK 0.005 w/v%  METHOCEL ®⁽¹⁾ 0.1 w/v % Carbopol⁽²⁾ 0.2 w/v % pH 6.4 water q.s. 100%

Composition 11

Ofloxacin 0.3 w/v % BAK 0.005 w/v %  METHOCEL ®⁽¹⁾ 0.1 w/v % Carbopol⁽²⁾0.225 w/v %  Glycerine 2.6 w/v % pH 6.5 water q.s. 100%

-   -   (1) Methyl cellulose    -   (2) One of a series of polymers 2-propenoic acid cross-linked        with alkyl ethers of pentaerythritol

An abbreviated preservative efficacy test of each of these compositionsis performed using S. aureus ATCC 6538 and A. niger ATCC 16404 as thetest organisms. The compositions are tested against Ph Eur-A/B and USPcriteria according to ARM T-005. Ten (10) milliliter of each compositionis challenged with approximately 10⁵ cfu/ml of test organism. At theappropriate time intervals, the amount of bacterial and fungal survivorsare assayed using Dey Engley broth (DE) as the neutralizer media. DE,along with filtration, is sufficient at neutralizing the antimicrobialagents in the compositions. One (1) ml of each sample is diluted intonine (9) ml of DE. One (1) of the 1:10 dilution is filtered through a0.45 μm filter and washed with 100 ml saline/TWEEN® 80. After washingthe filter a second time with 100 ml of a saline/TWEEN® 80 solution, thefiltrate is placed onto a TSA plate for bacteria and SAB for fungi. Thesame procedure as stated above was followed for composition 11 (which isin the form of a gel) except a 1:100 dilution of the product is madeprior to filtration (0.1 ml of product is added to 10 ml DE).

A summary of the results of these preservative efficacy tests is asfollows:

Composition USP Ph Eur-A Ph Eur-B 1 PASS FAIL Marginal PASS 2 PASS FAILFAIL 3 PASS FAIL Marginal PASS 4 PASS FAIL PASS 5 PASS FAIL FAIL 6 PASSFAIL FAIL 7 PASS PASS Marginal PASS 8 PASS FAIL PASS 9 PASS PASS PASS 10PASS PASS PASS 11 PASS PASS PASS

Derailed results of the preservative efficacy tests were as follows:

Test Organism Inoculum Test Compositions level Interval 1 2 3 4 5 6 S.aureus  6 hours 2 × 10⁵ 9 × 10⁴ 1 × 10⁵ 8 × 10⁴ 8 × 10⁴ 1 × 10⁵ ATTC6538 24 hours 7 × 10⁴ 3 × 10⁴ 6 × 10⁴ <10 8 × 10³ 2 × 10³ 4 × 10³  7days <10 <10 <10 1 × 10¹ <10 <10 14 days <10 <10 <10 <10 <10 <10 28 days<10 <10 <10 <10 <10 <10 A. niger  7 days 8 × 10⁴ 8 × 10⁴ 4 × 10³ 1 × 10³7 × 10⁴ 7 × 10⁴ ATCC 16404 14 days 2 × 10⁴ 3 × 10⁴ 2 × 10³ 1 × 10³ 9 ×10⁴ 9 × 10⁴ 1 × 10³ 28 days 1 × 10⁴ 3 × 10⁴ 2 × 10³ 8 × 10

2 × 10⁴ 1 × 10⁴

indicates data missing or illegible when filed

Test Organism Inoculum Test Compositions level Interval 7 8 9 10 11 S.aureus  6 hours 1 × 10⁵ 1 × 10⁵ <10 <10 <10 ATTC 6538 24 hours 3 × 10³ 1× 10⁴ <10 <10 <10 4 × 10³  7 days <10 <10 <10 <10 <10 14 days <10 <10<10 <10 <10 28 days <10 <10 <10 <10 <10 A. niger  7 days 2 × 10⁴ 3 × 10³1 × 10¹ <10 1 × 10¹ ATCC 16404 14 days 2 × 10⁴ 7 × 10³ <10 <10 <10 1 ×10

28 days 4 × 10² 1 × 10² <10 <10 <1 

indicates data missing or illegible when filed

The present compositions very effectively pass the USPET. In particular,the fact that Compositions 1 to 8, which include no component known tobe effective as a preservative, pass the USPET is surprising, especiallysince prior art compositions which have included a quinolone, such asofloxacin, have included preservatives, such as BAK. In addition,Compositions 1 to a do have sufficient antifungal activity to prevent A.niger from increasing in population. Thus, the quinolone, ofloxacin,included in these compositions has sufficient fungistatic activity toact as a preservative for the composition against A. nigercontamination.

EXAMPLES 12 TO 23

A further series of compositions, Compositions 12 to 24, are prepared byblending various components together. These compositions have thefollowing chemical make-ups. Each composition included sufficient waterto total 100% by weight.

EXAMPLE NO. ACTIVES CONCENTRATION, w/v % 12 Ketorolac 0.5 Ofloxacin 0.3NaCl 0.79 pH 6.4 13 Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.30 EDTA 0.1 BoricAcid 1.0 pH 6.4 14 Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 BAK 0.005 pH6.4 15 Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 pH 7.4 16 Ketorolac 0.5Ofloxacin 0.3 NaCl 0.79 BAK 0.005 pH 7.6 17 Ketorolac 0.5 Ofloxacin 0.3NaCl 0.79 BAK 0.005 Octoxynol⁽³⁾ 0.007 pH 6.4 18 Ketorolac 0.5 Ofloxacin0.3 NaCl 0.79 BAK 0.005 Octoxynol⁽³⁾ 0.007 pH 7.6 19 Ketorolac 0.5Ofloxacin 0.3 NaCl 0.79 BAK 0.005 Cyclodextrin⁽⁴⁾ 0.1 pH 6.4 20Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 BAK 0.005 Cyclodextrin⁽⁴⁾ 0.1 pH7.6 21 Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 Purite⁽⁵⁾ 0.007 pH 7.6 22Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 Purite⁽⁵⁾ 0.007 Octoxynol⁽³⁾ 0.007pH 7.6 23 Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 Purite⁽⁵⁾ 0.007Cyclodextrin⁽⁴⁾ 0.1 pH 7.6 ⁽³⁾Polyethylene glycol mono(octylphenyl)ether⁽⁴⁾7-sulfobutylether beta-cyclodextrin ⁽⁵⁾Stabilized chlorine dioxide

The samples were tested for preservative efficacy against Ph Eur-A/B andUSP criteria according to ARM T-005. Ten (10) milliliters of each samplewas challenged with approximately 10⁵ cfu/ml of test organism. The testorganisms included S. aureus ATCC 6538, P. aeruginosa ATCC 9027, E. coliATCC 8739, C. albicans ATCC 10231, and A. niger ATCC 16404. At theappropriate time intervals, the amount of bacterial and fungal survivorswere assayed using DE as the neutralizer media. DE, along withfiltration, is sufficient at neutralizing the antimicrobial agents inthe compositions. One (1) ml of each sample was diluted into 9 ml of DE.The whole 10 ml was filtered through a 0.45 μm filter and washed with100 ml of phosphate buffered saline pH 5.4. After washing the filter asecond time with 100 ml phosphate buffered saline/TWEEN® 80, the filterwas placed onto a blood agar plate for bacteria and SAB for fungi.

The results are summarized in the below table.

SAMPLE ID USP Ph Eur-A Ph Eur-B 12 PASS FAIL FAIL 13 PASS FAIL FAIL 14PASS PASS PASS 15 PASS FAIL FAIL 16 PASS PASS PASS 17 PASS PASS PASS 18PASS PASS PASS 19 PASS FAIL PASS 20 PASS PASS PASS 21 PASS FAIL FAIL 22PASS FAIL FAIL 23 PASS FAIL FAIL

Detailed results of the preservation efficacy tests on Compositions 12to 17 were as follows:

Test Organism Inoculum Composition level Test Interval 12 13 14 15 16 17S. aureus  6 hours 2 × 10⁵ 2 × 10⁵  4 3 × 10⁵ <10  1 ATTC 6538 24 hours2 × 10⁵ 2 × 10⁵ <10 3 × 10⁵ <10 <10 5 × 10⁵  7 days <10 2 × 10¹ <10 <10<10 <10 14 days <10 <10 <10 <10 <10 <10 28 days <10 <10 <10 <10 <10 <10P. aeruginosa  6 hours <10 <10 <10 <10 <10 <10 ATCC 9027 24 hours <10<10 <10 <10 <10 <10 3 × 10⁵  7 days <10 2 × 10¹ <10 <10 <10 <10 14 days<10 <10 <10 <10 <10 <10 28 days <10 <10 <10 <10 <10 <10 E. coli  6 hours6 × 10¹ 5 × 10¹ <10 5 × 10¹ <10 <10 ATCC 8739 24 hours 5 × 10² <10 <10<10 <10 <10 5 × 10⁵  7 days <10 <10 <10 <10 <10 <10 14 days <10 <10 <10<10 <10 <10 28 days <10 <10 <10 <10 <10 <10 C. albicans  7 days 1 × 10⁵2 × 10⁵ <10 3 × 10⁵ <10 <10 ATCC 10231 14 days 1 × 10⁵ 2 × 10⁵ <10 1 ×10⁵ <10 <10 3 × 10⁵ 28 days 8 × 10⁴ 9 × 10⁴ <10 9 × 10⁴ <10 <10 A. niger 7 days 6 × 10⁴ 6 × 10⁴ 3 × 10¹ 7 × 10⁴ <10 3 × 10¹ ATCC 16404 14 days 4× 10⁴ 3 × 10⁴  4 6 × 10⁴ 1 × 10² <10 1 × 10⁵ 28 days 3 × 10⁴ 3 × 10⁴ <104 × 10⁴ <10 <10

Certain embodiments of the present compositions, that is Compositions 12and 15, include no component known to be effective as a preservative.These compositions do, however, pass the USPET. In addition, althoughCompositions 12 and 15 do not pass the European Preservative EfficacyTests, they do have sufficient antifungal activity to prevent C.albicans and A. niger from increasing in population. The quinolone,ofloxacin, included in these compositions has sufficient fungistaticactivity to act as a preservative for the composition against C.albicans and A. niger contamination. Further, Compositions 21, 22 and 23include stabilized chlorine dioxide which is known to be an effectivepreservative in ophthalmic formulations. However, such compositions alsodo not pass the European Preservative Efficacy Tests.

EXAMPLES 24 TO 33

Compositions 1 to 8, 12 and 15, in the form of solutions, are eachadministered to a human eye which has a microbial infection. Eachcomposition is administered in an amount of about 1 to 2 drops per eyewith the drops containing about 25 to 50 micro liters of thecomposition. The drops are administered 3 to 4 times per day.

After a week of such administering, each of the eyes treated is free ofthe microbial infection.

EXAMPLES 34 TO 39

Each of the Compositions 5 to 8, 12 and 15 are administered to an eyewhich has been subjected to surgical trauma. Before administration, eacheye exhibits a degree of inflammation and is the source of a degree ofpain.

Each composition is administered to the eye in an amount of about 1 to 2drops per eye with the drops containing about 25 to 50 micro liters. Thedrops are administered 3 to 4 times per day.

After a week of such administering, each of the eyes treated exhibits noinflammation and is not a source of pain. In addition, each of the eyeshas remained free of microbial infection.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

1-35. (canceled)
 36. An ophthalmically acceptable composition comprisingfrom about 0.15% to about 1.1% of a quinolone antibiotic present in atherapeutically effective amount, wherein said composition containssubstantially no additional components which are effective aspreservatives, is self-preserved, and is suitable for topicalapplication to the eye.
 37. The composition of claim 36 wherein saidquinolone is a halogenated quinolone antibiotic.
 38. The composition ofclaim 36 wherein the quinolone is a fluorinated quinolone antibiotic.39. The composition of claim 36 in a liquid form.
 40. The composition ofclaim 36 in a gel form.
 41. The composition of claim 36 in a solid form.42. The composition of claim 36 which contains a water soluble polymer.43. The composition of claim 42 wherein said water soluble polymer is acellulose derivative.
 44. The composition of claim 36, wherein saidcomposition contains sufficient preservative efficacy to pass the U.S.Preservative Efficacy Test.
 45. A method of treating an ocular infectionwithout substantial irritation caused by added preservatives comprisingadministering to a mammalian eye an ophthalmically acceptable solutioncomprising from about 0.15% to about 1.1% of a quinolone antibioticpresent in a therapeutically effective amount, wherein said compositioncontains substantially no additional components which are effective aspreservatives, and is self-preserved.
 46. The method of claim 45 whereinthe composition comprises a water soluble polymer.
 47. The method ofclaim 46 wherein the water soluble polymer is a cellulose derivative.48. The method of claim 45 wherein the quinolone antibiotic is ahalogenated quinolone.
 49. The method of claim 48 wherein the quinoloneantibiotic is a fluorinated quinolone.
 50. The method of claim 45wherein said composition contains sufficient preservative efficacy topass the U.S. Preservative Efficacy Test.
 51. The method of claim 45wherein said composition is administered topically.